Dip-coating process for preparing cellulose ether capsule shells

ABSTRACT

The dip-coating process for preparing cellulose ether film products is improved by (A) dipping a die mandrel with an electrically conductive outer surface into an aqueous thermal gelling solution containing at least 20 wt. percent of a filmforming hydroxyalkyl alkyl cellulose ether, (B) removing the coated die mandrel from the aqueous solution, (C) rapidly converting the coating into a nonflowing cellulose ether gel by induction heating, and thereafter (D) drying the gelled coating to form a stable film product. This process is particularly useful in making water-soluble, pharmaceutical capsule shells.

United States Patent Cyril A. J. Langman Midland, Mich.

[211 App]. No. 833,715

[22] Filed June 16, 1969 [45] Patented Nov. 2, 1971 [73] Assignee TheDow Chemical Company Midland, Mich.

[72] inventor [54] DIP-COATING PROCESS FOR PREPARING CELLULOSE ETHERCAPSULE SHELLS 6 Claims, No Drawings [52] U.S. Cl 264/25, 106/197, 117/932, 264/301, 264/D1G. 37, 264/D1G. 46 [51] int. Cl B29c 13/00 [50]Field of Search 264/301,

25, DIG. 41, DIG. 1, DIG. 37; 106/197; 117/932,

[561 References Cited UNITED STATES PATENTS 3,315,016 4/1967 Wersosky eta1 264/25 3,493,407 2/1970 Greminger et al. 264/301 FOREIGN PATENTS1,010,389 1965 Great Britain 264/301 Primary Examiner-Robert F. WhiteAssistant ExaminerGene Auville Attorneys-Griswold & Burdick and D. B.Kellom ABSTRACT: The dip-coating process for preparing celluloseDIP-COATING PROCESS FOR PREPARING CELLULOSE ETIIER CAPSULE SHELLSBACKGROUND Pharmaceutical capsule shells have long been made of gelatinin spite of the recognized deficiencies of gelatin shells at very low orhigh humidity. No other material has yet met the rigid requirements forcommercial acceptance.

Water-soluble, film-forming cellulose ethers have been suggested. Thusin U.S. Pat. No. 2,526,683 Murphy describes the preparation ofmethylcellulose capsules by a process involving thermal gelation of anaqueous cellulose ether solution on a preheated capsule forming pin.Greminger and Weaver in U.S. Pat. No. 2,8l0,659 describe plasticizedcellulose ether compositions suitable for molding or extruding intoflexible films and capsules. However, mechanical problems and poorcapsule properties have prevented commercial use of these processes.

STATEMENT OF THE INVENTION An improved dip-coating process has now beendiscovered in which elimination of thermal gelation in the coating bath,use of certain low-viscosity hydroxyalkyl cellulose ethers, and rapidimmobilization of the dip coating by induction heating after removalfrom the coating bath are critical elements. More specifically, theimproved process comprises: (A) dipping a die mandrel having anelectrically conductive outer surface and a surface temperature belowthe gel point temperature of the coating solution into an aqueousthermal gelling coating solution having a viscosity of about 1,000-12,000 cps. and containing at least wt. percent of a film-forming C,-C,hydroxyalkyl C,--C alkyl cellulose ether characterized by a hydroxyalkylM.S. of about 0.07-l.0, an alkyl D.S. of about 0.6-2.0, and a viscosityof about 2-20 cps. as a 2 wt. percent aqueous solution at 20 C.; (B)removing the coated die mandrel from the aqueous coating solution; (C)rapidly converting the cellulose ether coating into a nonflowing gel byinduction heating; and thereafter (D) drying the gelled coating to forma stable cellulose ether film product.

By preventing thermal gelation in the dip-coating bath, a more uniform,clean-breaking, coating of the die mandrel is obtained. But once removedfrom the bath, the cellulose ether coating is rapidly gelled byinduction heating to provide a stable, nonflowing and uniform coating.Final drying provides a hard and strong cellulose ether film productquite suitable for pharmaceutical applications. These products have goodfilm clarity and rate of dissolution, yet they remain firm and sturdyunder conditions of extreme humidity.

GENERAL DESCRlPTlON-DlP-COATING BATH Murphy, U.S. PAt. No. 2,526,683describes the general requirements for an aqueous dip-coating bath of athermal gelling cellulose ether. To obtain a dry film thickness of about4-5 mils in a single dip operation, the bath must contain at least 20wt. percent of the cellulose ether and have an operational viscosity ofabout l,000-l2,000 cps. This requires a water-soluble cellulose etherwith a standard 2 percent aqueous solution viscosity of about 2-20 cps.,preferably about 2-7 cps. Particularly effective is a bath having aviscosity of about l,000-4,000 cps. at a dip-coating temperature ofabout C.

Typical of the water-soluble, film-forming cellulose ethers used hereinare hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, andhydroxyethyl ethyl cellulose. Particularly suitable are cellulose ethershaving a C,-C hydroxyalkyl M.S. of about 0.7-1.0 and a C C- alkyl D.S.of about 0.6-2.0. Most desirable for pharmaceutical applications becauseof film clarity and water solubility are cellulose ethers having ahydroxypropyl M.S. of about 0.15-0.35 and a methyl D.S. of about1.8-2.0. The terms M.S. (molar substitution) and D.S. (degree ofsubstitution) are used as defined in Klug U.S. Pat. No. 3,357,971.

(1957). The more concentrated aqueous solutions used in' 'th'e'pfsen'tprocesshave apams'ndihaii about l0-20 lower than the 2 percentsolutions. Stiff, immobilized and nonflowing gels are obtained when theconcentrated aqueous solution is heated to a few degrees above its gelpoint. For example, a hydroxypropyl methyl cellulose with a 2 percentsolution gel point of about 60 C.; as a 25 percent solution has a gelpoint of about 42 C. and forms a firm nonflowing gel at 45-46 C. Furthercontrol of the dip-coating solution gel point can be obtained usingconventional cellulose ether gelation additives such as NaCl, Na,SO,,Na,CO,, Na PO,, MgCh, Al,(SO.) urea, etc.

Normally the temperature of the dip-coating bath is held about 5-l0 C.below its gel point temperature. Under these conditions effective dipcoating is obtained by immersing a die mandrel having a surfacetemperature below the thermal gel point of the bath into the bath andthen smoothly removing the coated die from the bath allowing the excesscoating solution to drain from the die as it separates from the bath.

A critical element in the present process is the rapid immobilization ofthe cellulose ether coating after removal from the dip-coating bath.Unless the coating is rapidly immobilized on the die surface, thecoating uniformity will be lost with formation of flow bulges or tires.Particularly in preparing pharmaceutical capsule shells, extreme coatinguniformity is required.

Attempts to immobilize the coating by conventional heating methods usingpreheated air, infrared heaters, dielectric heaters, electric resistanceheaters, all failed to provide the requisite rapid, direct and flexibleheating required for a commercial dip coating operation. However,induction heating was found to be highly effective giving gelation andimmobilization of the coating in a few seconds.

induction heating uses a skin-effect phenomena observed when anelectroconductive object is placed within an electromagnetic fieldformed by the flow of rapidly alternating current in a coil. As appliedto the dip-coating process, the coated die mandrel immediately afterremoval from the cellulose ether bath passes into an induction heaterunit. The electric currents induced in the die mandrel heat its surfaceand rapidly raises the temperature of the aqueous cellulose ethercoating above its gel point. Thus the coating is effectively and rapidlyimmobilized. Thereafter further drying of the gelled coating can becarried out by any desired method without distortion of the coatingfilm, a critical requirements in producing capsule shells.

To permit induction heating, the die mandrel must have an outer surfaceof an electrically conductive metal such as aluminum, brass, copper,steel or titanium. Magnetic metals are particularly effective since themagnetic permeability generally results in higher induction heatingsurface temperatures. Particularly suitable in the manufacture ofcapsule shells are stainless steel pins which can be machined to a closetolerance and mounted on a nonconductive support.

A suitable induction heater comprises a copper coil energized by asingle-phase alternating current. In general, a

. frequency range of about ZOO-5,000 kilocycles per second,

preferably about 250-400 kc./sec. is suitable for rapid gelation of thecellulose ether dip coating. Further details on induction heating ofconductive metals are given in Faeknerea U.S. Pat. No. 2,902,572 and AlfU.S. Pat. No. 3,041,434, for example.

Since the induced currents are concentrated near the surface of the diemandrel, it becomes a'highly efficient and selective heating source forthe thermal gelation of the cellulose ether. A further advantage of theinduction heater is that no physical contact is required between theenergy source and the object to be heated, thus lending flexibility tothe system design and operation.

By appropriate control of the frequency and field strength, effectivethermal gelation can be achieved in about 1-30 see. Thereafter thegelled cellulose ether coating held at a tem perature above its gelpoint can be dried in any convenient manner, such as a hot-air kiln,until a firm, essentially waterfree film or coating is obtained. In theproduction of pharmaceutical capsules, the dried cellulose ether capsuleshells are removed from the die mandrel, trimmed and assembled.

Normally the cellulose ether films or coatings are relatively clear andtransparent. However, if opaque capsules are desired, a minor amount ofinert nontoxic pigment such as powdered charcoal or finely dividedtitanium dioxide can be incorporated in the coating composition.Conventional nontoxic dyes and fillers can also be used. For increasedflexibility, an appropriate plasticizer such as glycerine, propyleneglycol, or hydroxypropyl glycerine can be included in a moderate amount,e.g., to 20 percent.

This process is particularly suited for preparing pharmaceutical capsuleshells which dissolve at a rate comparable to gelatin capsules. Delayrelease characteristics can be obtained by incorporation of a lesswater-soluble cellulose ether such as ethyl cellulose as described byGreminger and Windover US. Pat. No. 2,887,440.

To illustrate further the present invention, the following examples aregiven. Unless otherwise specified, all parts and percentages are byweight. Solution viscosities are determined by the method of ASTM D-l347-64 unless otherwise stated.

EXAMPLE 1 A. An aqueous dip-coating solution was prepared by dissolving250 parts of hydroxypropyl methyl cellulose in 750 parts water at roomtemperature. The hydroxypropyl methyl cellulose used had a 2' percentaqueous solution viscosity of 5 cps. at 20 C. and a thermal gel point ofabout 60 C. Its hydroxypropyl M.S. was about 0.15-0.35 and its methoxylD.S. about 1.8-2.0. The clear 25 percent aqueous solution had aviscosity of 3,500 cps.at 25 C. measured at a shear rate of 30 sec." ona I-laake Rotovisco viscometer. Its gel point was about 4 l -2 C. with afirm, rigid gel being obtained at 43-45 C.

B. Capsule shells were prepared from this aqueous cellulose ethersolution using No. 0 capsule pins machined from Type 3 l3 stainlesssteel and lightly coated with a cotton seed oil lubricant grease. Thepins, mounted on a nonelectrically conducting bar, were dipped into thecellulose ether solution at room temperature for -15 seconds. Then theywere smoothly withdrawn from the solution allowing the excess to stripfrom the coated pin.

The coated pins were then immediately inverted and placed in a 5 kw.induction heater coil about cm. long and 10 cm. in diameter andconsisting of 12 turns of 6-8 mm. copper tubing connected to a 450kilocycle per second alternating current source. In less than seconds,the cellulose ether coating had gelled to an immobile form. Final dryingwas achieved in a warm-air oven at 50-60 C.

The resulting capsule shells stripped from the pins had a uniformthickness of about 4 mils with excellent retention of shape. Nosignificant formation of thick rings or tires from excessive rundownprior to gelation was observed. The shells were easily assembled intocapsules. Their dried equilibrium water content was about 5 wt. percentat room temperature and humidity.

EXAMPLE 2 In another, test, the percent aqueous hydroxypropyl methylcellulose solution described in example 1 was modified by addition of1.1 wt. percent sodium sulfate to give a solution with a gel point ofabout 33 C. Capsuleshells prepared from this solution turned opaque whengelled by induction heating and remained opaque when dry. Their driedshell thickness and shape were very uniform.

EXAMPLE 3 Further tests with a 5 kilowatt induction heater indicatedthat with continuous application of power, an immobile gel was obtainedin about 5-10 seconds. Other thermal gelling hydroxyalkyl alkylcellulose ethers applied as 20-40 weight percent aqueous solutions gavesimilar results when the die mandrels were placed in an induction heatercoil after dip.

coating.

I claim:

1. In a process for preparing ingestible, water-soluble cellulose etherpharmaceutical capsule shells by dip coating a die mandrel with anaqueous, film-forming cellulose ether solution, the improvement whichcomprises:

A. Dipping a die mandrel having an electrically conductive outer surfaceand a surface temperature below the gel point temperature of the coatingsolution into an aqueous thermal gelling coating solution containing atleast 20 wt. percent of a film-forming C -C hydroxyalkyl C -C, alkylcellulose ether, said solution having a viscosity of about 1,000-1 2,000cps;

B Removing the coated die mandrel from the aqueous coating solution andimmediately placing it in an induction heating zone;

C. Rapidly converting the cellulose ether coating into a nonflowingthermal gel by induction heating in a magnetic field generated by aninduction heating coil operation at a frequency of about 200-5 ,000kilocycles per second; and thereafter D. Drying the gelled coating toform a stable, ingestible, water-soluble cellulose ether pharmaceuticalcapsule shell.

2. The process of claim 1 where the cellulose ether is ahydroxypropylmethyl cellulose having a hydroxypropyl M.S of about0.15-0.35, a methyl D.S. of about 18-20, and a 2 percent aqueoussolution viscosity of about 2-7 cps. at 20 C.

3. The process of claim 2 where the coating solution contains about25-35 wt. percent of the hydroxypropylmethyl cellulose and has aviscosity of about l,000-4,000 cps. at the dipcoating temperature.

4. The process of claim I where the die mandrel is made of stainlesssteel.

5. The process of claim 1 where the induction heater operates at afrequency of about 250-400 kilocycles per second.

6. The process of claim I where pharmaceutical capsule shells areprepared by: (A) Dip coating a stainless steel die mandrel with a 25-35wt. percent aqueous solution of a hydroxypropylmethyl cellulosecharacterized by a hydroxypropyl M.S. of about 0.15-0.35, a methyl D.S.of about l.8-2.0, and a 2 percent aqueous solution viscosity of about2-7 cps. at 20 C. (B) removing the coated die mandrel from the celluloseether solution and immediately placing it in an induction heating zone;(C) rapidly converting the cellulose ether coating into a nonflowing gelby induction heating in a magnetic field generated by an inductionheating oil operating at a frequency of about ZOO-5,000 kilocycles persecond; (D) drying the gelled cellulose ether coating in a hot-air oven;and (E) stripping the capsule shell from the die mandrel.

23x3 UNI'IED STATES PATENT OFFICE CERTIFICATE OF CORRECTIGN Patent No.3,6 7,5 8 Dated 2 Nov. 1971 Inventor(s) Cyril A. J. Langman It iscertified that error appears in the above-ideritifie'd patent and thatsaid Letters Patent are hereby corrected as shown below:

In column 2, line delete W999" and insert g9 99 In column 3, line 38,delete "sec. and insert sec.

Signed and sealed this 2nd day of May 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Co issioner ofPatents

2. The process of claim 1 where the cellulose ether is ahydroxypropylmethyl cellulose having a hydroxypropyl M.S of about 0.15-0.35, a methyl D.S. of about 1.8- 2.0, and a 2 percent aqueous solutionviscosity of about 2-7 cps. at 20* C. PG,11
 3. The process of claim 2where the coating solution contains about 25- 35 wt. percent of thehydroxypropylmethyl cellulose and has a viscosity of about 1,000- 4,000cps. at the dip-coating temperature.
 4. The process of claim 1 where thedie mandrel is made of stainless steel.
 5. The process of claim 1 wherethe induction heater operates at a frequency of about 250- 400kilocycles per second.
 6. The process of claim 1 where pharmaceuticalcapsule shells are prepared by: (A) Dip coating a stainless steel diemandrel with a 25-35 wt. percent aqueous solution of ahydroxypropylmethyl cellulose characterized by a hydroxypropyl M.S. ofabout 0.15- 0.35, a methyl D.S. of about 1.8- 2.0, and a 2 percentaqueous solution viscosity of about 2-7 cps. at 20* C. (B) removing thecoated die mandrel from the cellulose ether solution and immediatelyplacing it in an induction heating zone; (C) rapidly converting thecellulose ether coating into a nonflowing gel by induction heating in amagnetic field generated by an induction heating oil operating at afrequency of about 200-5,000 kilocycles per second; (D) drying thegelled cellulose ether coating in a hot-air oven; and (E) stripping thecapsule shell from the die mandrel.